Activation of the MyD88 signaling pathway inhibits ischemia-reperfusion injury in the small intestine

Toll-like receptors (TLRs) recognize microbial components and trigger the signaling cascade that activates innate and adaptive immunity. Recent studies have shown that the activation of TLR-dependent signaling pathways plays important roles in the pathogenesis of ischemia-reperfusion (I/R) injuries in many organs. All TLRs, except TLR3, use a common adaptor protein, MyD88, to transduce activation signals. We investigated the role of MyD88 in I/R injury of the small intestine. MyD88 and cyclooxygenase-2 (COX-2) knockout and wild-type mice were subjected to intestinal I/R injury. I/R-induced small intestinal injury was characterized by infiltration of inflammatory cells, disruption of the mucosal epithelium, destruction of villi, and increases in myeloperoxidase activity and mRNA levels of TNF-α and the IL-8 homolog KC. MyD88 deficiency worsened the severity of I/R injury, as assessed using the histological grading system, measuring luminal contents of hemoglobin (a marker of intestinal bleeding), and counting apoptotic epithelial cells, while it inhibited the increase in mRNA expression of TNF-α and KC. I/R significantly enhanced COX-2 expression and increased PGE2 concentration in the small intestine of wild-type mice, which were markedly inhibited by MyD88 deficiency. COX-2 knockout mice were also highly susceptible to intestinal I/R injury. Exogenous PGE2 reduced the severity of injury in both MyD88 and COX-2 knockout mice to the level of wild-type mice. These findings suggest that the MyD88 signaling pathway may inhibit I/R injury in the small intestine by inducing COX-2 expression.

Download Full-text

A1 adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis

AJP Renal Physiology ◽

10.1152/ajprenal.00470.2004 ◽

2005 ◽

Vol 289 (2) ◽

pp. F369-F376 ◽

Cited By ~ 57

Author(s):

George Gallos ◽

Thomas D. Ruyle ◽

Charles W. Emala ◽

H. Thomas Lee

Keyword(s):

Organ Dysfunction ◽

Knockout Mice ◽

Adenosine Receptor ◽

Ischemia Reperfusion ◽

Cecal Ligation ◽

Intercellular Adhesion Molecule ◽

Myeloperoxidase Activity ◽

Wild Type ◽

Wild Type Littermate ◽

Septic Peritonitis

Sepsis is a leading cause of multiorgan dysfunction and death in hospitalized patients. Dysregulated inflammatory processes and apoptosis contribute to the pathogenesis of sepsis-induced organ dysfunction and death. A1 adenosine receptor (A1AR) activation reduces inflammation and apoptosis after ischemia-reperfusion injury. Therefore, we questioned whether A1AR-mediated reduction of inflammation and apoptosis could improve mortality and organ dysfunction in a murine model of sepsis. A1AR knockout mice (A1 knockout) and their wild-type (A1 wild-type) littermate controls were subjected to cecal ligation and double puncture (CLP) with a 20-gauge needle. A1 knockout mice or A1 wild-type mice treated with 1,3-dipropyl-8-cyclopentylxanthine (a selective A1AR antagonist) had a significantly higher mortality rate compared with A1 wild-type mice following CLP. Mice lacking endogenous A1ARs demonstrated significant elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and tumor necrosis factor-α 24 h after induction of sepsis compared with wild-type mice. The renal corticomedullary junction from A1 knockout mice also exhibited increased myeloperoxidase activity, intercellular adhesion molecule-1 protein, and mRNA encoding proinflammatory cytokines compared with renal samples from A1 wild-type littermate controls. No difference in renal tubular apoptosis was detected between A1 knockout and A1 wild-type mice. We conclude that endogenous A1AR activation confers a protective effect in mice from septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.

Download Full-text

The transcription factor interferon regulatory factor-1 mediates liver damage during ischemia-reperfusion injury

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00460.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. G1261-G1268 ◽

Cited By ~ 50

Author(s):

Allan Tsung ◽

Michael T. Stang ◽

Atsushi Ikeda ◽

Nathan D. Critchlow ◽

Kunihiko Izuishi ◽

...

Keyword(s):

Transcription Factor ◽

Liver Injury ◽

Liver Damage ◽

Knockout Mice ◽

Ischemia Reperfusion ◽

Wild Type ◽

Regulatory Factor ◽

Hepatic Ischemia ◽

Adenoviral Delivery ◽

Tnf Α

Hepatic ischemia occurs in the settings of trauma, transplantation, and elective liver resections. The initiating events that account for local organ damage are only partially understood. Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that regulates the expression of a number of genes involved in both innate and acquired immunity; however, its function in liver injury is unknown. Therefore, the purpose of this study was to investigate the role of IRF-1 in hepatic ischemia-reperfusion (I/R) injury. In C57BL/6 mice undergoing 60 min of hepatic ischemia, IRF-1 protein expression increased as early as 1 h after reperfusion. IRF-1 knockout mice were significantly protected from hepatic I/R-induced damage compared with their wild-type controls. Hepatic I/R injury resulted in marked activation of the MAP kinase c-Jun NH2-terminal kinase (JNK) in wild-type mice but not IRF-1 knockout mice. IRF-1 knockout mice also exhibited significantly lower hepatic expression of TNF-α, IL-6, ICAM-1, and inducible nitric oxide synthase (iNOS) mRNA. Adenoviral delivery of IRF-1 into C57BL/6 mice resulted in increased liver damage even without an ischemic insult. This injury was associated with increased JNK activation and hepatic iNOS expression. Because IRF-1 contributed to liver injury, we also examined for inflammatory signals that regulated IRF-1 gene expression in cultured hepatocytes. Whereas IFN-γ and IFN-β were strong inducers of IRF-1 mRNA (>10-fold) in a time- and dose-dependent manner, TNF-α and IL-1β also induced IRF-1 mRNA to a lesser extent (2- to 3-fold). IL-6 and lipopolysaccharide had no effect on IRF-1 expression. This study demonstrates that IRF-1 exerts a harmful role in hepatic I/R injury by modulating the expression of multiple inflammatory mediators. We further show that IRF-1-mediated injury involves the activation of JNK and that hepatocellular IRF-1 expression itself is regulated by specific cytokines.

Download Full-text

Remote ischemic per-conditioning protects against renal ischemia–reperfusion injury via suppressing gene expression of TLR4 and TNF-α in rat model

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2018-0543 ◽

2019 ◽

Vol 97 (2) ◽

pp. 112-119 ◽

Cited By ~ 3

Author(s):

Firouzeh Gholampour ◽

Jamshid Roozbeh ◽

Sahar Janfeshan ◽

Zeinab Karimi

Keyword(s):

Reperfusion Injury ◽

Signaling Pathway ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Renal Ischemia ◽

Antioxidant Systems ◽

Tlr4 Signaling ◽

Tnf Α ◽

Renal Ischemia Reperfusion Injury ◽

Tlr4 Signaling Pathway

The pathogenesis of renal ischemia–reperfusion injury (IRI) involves both inflammatory processes and oxidative stress in the kidney. This study determined whether remote ischemic per-conditioning (RIPerC) is mediated by toll-like receptor 4 (TLR4) signaling pathway in rats. Renal IR injury was induced by occluding renal arteries for 45 min followed by 24 h of reperfusion. RIPerC included 4 cycles of 2 min of ischemia of the left femoral artery followed by 3 min of reperfusion performed at the start of renal ischemia. Rats were divided into sham, IR, and RIPerC groups. At the end of the reperfusion period, urine, blood and tissue samples were gathered. IR created kidney dysfunction, as ascertained by a significant decrease in creatinine clearance and a significant increase in sodium fractional excretion. These changes occurred in concert with a decrease in the activities of glutathione peroxidase, catalase, and superoxide dismutase with an increment in malondialdehyde levels, mRNA expression levels of TLR4 and tumor necrosis factor α (TNF-α), and histological damage in renal tissues. RIPerC treatment diminished all these changes. This study demonstrates that RIPerC has protective effects on the kidney after renal IR, which might be related to the inhibition of the TLR4 signaling pathway and augmentation of antioxidant systems.

Download Full-text

Local anesthetic Ropivacaine protects rats from myocardial ischemia/reperfusion injury by inhibition of COX-2

Archives of Medical Science ◽

10.5114/aoms/132472 ◽

2021 ◽

Author(s):

Zhou Yu ◽

Sufang Sun ◽

Fang Hu

Keyword(s):

Oxidative Stress ◽

Creatine Kinase ◽

Ischemia Reperfusion ◽

Inos Expression ◽

Ischaemic Injury ◽

Cardiac Tissues ◽

Tnf Α ◽

Creatine Kinase Mb ◽

Cellular Apoptosis ◽

Cox 2

IntroductionMyocardial ischaemia/reperfusion (I/R) injury is the leading cause of morbidity and mortality worldwide. Despite novel advances in therapeutics, the management of myocardial I/R is still an unmet medical need. Therefore, in the present study, we have demonstrated the protective effect of ropivacaine (RPC) on the myocardial infarction in rats and its underlying mechanism.Material and methodsInitially, the effect of RPC was determined on the infarct size and histopathology of cardiac tissues. The effect of RPC was also determined on the levels of various cardiac biomarkers such as creatine kinase (CK), creatine kinase MB (CK-MB), alanine aminotransferase (ALT), asparganine aminotransferase (AST), and lactate dehydrogenase (LDH), and biomarkers of oxidative stress (MDA, SOD, and GSH) and inflammation (tumour necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and IL-6). RPC effect was also quantified on cellular apoptosis and COX-2 and iNOS expression via western blot analysis. The RPC was further docked into the active site of COX-2.ResultsIt has been found that RPC reduces the improves haemodynamics of (LVSP and ± dp/dtmax, and LVEDP), infarct percentage and architecture of cardiac tissues of rats. It also reduces the level of studies cardiac injury biomarkers together with a reduction of oxidative stress (MDA, SOD, and GSH) and inflammation (TNF-α, IL-1β, and IL-6). Upon administration of RPC, the rate of cellular apoptosis was found to be greatly reduced, with a reduction in COX-2 and iNOS expression. In docking analysis, RPC creates van der Waals forces and pi-interactions with Tyr381, Arg106, Val102, Leu345, Val509, Ser339, Leu338, Val335, Ala513, His75, and Leu517 at the catalytic site of COX-2.ConclusionsCollectively, our results demonstrated that ropivacaine showed significant benefit against myocardial ischaemic injury.

Download Full-text

Protective effect of Cordyceps sinensis extract on lipopolysaccharide-induced acute lung injury in mice

Bioscience Reports ◽

10.1042/bsr20190789 ◽

2019 ◽

Vol 39 (6) ◽

Cited By ~ 6

Author(s):

Shuiqiao Fu ◽

Weina Lu ◽

Wenqiao Yu ◽

Jun Hu

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Protective Effect ◽

Weight Ratio ◽

Cordyceps Sinensis ◽

Myeloperoxidase Activity ◽

Mrna Levels ◽

Dependent Manner ◽

Tnf Α ◽

Cox 2

Abstract Background: To study the protective effect of Cordyceps sinensis extract (Dong Chong Xia Cao in Chinese [DCXC]) on experimental acute lung injury (ALI) mice. Methods and results: ALI model was induced by intratracheal-instilled lipopolysaccharide (LPS, 2.4 mg/kg) in BALB/c male mice. The mice were administrated DCXC (ig, 10, 30, 60 mg/kg) in 4 and 8 h after receiving LPS. Histopathological section, wet/dry lung weight ratio and myeloperoxidase activity were detected. Bronchoalveolar lavage fluid (BALF) was collected for cell count, the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and nitric oxide (NO) in BALF was detected by ELISA, the protein and mRNA expression of nuclear factor-κB p65 (NF-κB p65), inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in lung tissue was detected by Western blot and RT-PCR. The result showed that DCXC could reduce the degree of histopathological injury, wet/dry weight ratio (W/D ratio) and myeloperoxidase activity (P<0.05) with a dose-dependent manner. The increased number of total cells, neutrophils and macrophages in BALF were significantly inhibited by DCXC treatment (P<0.05). The increased levels of TNF-α, IL-1β, IL-6 and NO in BALF after LPS administration was significantly reduced by DCXC (P<0.05). In addition, the increased protein and mRNA levels of iNOS, COX-2 and NF-κB p65 DNA binding ability in LPS group were dose-dependently reduced by DCXC treatment (P<0.05). Conclusion: DCXC could play an anti-inflammatory and antioxidant effect on LPS-induced ALI through inhibiting NF-κB p65 phosphorylation, and the expression of COX-2 and iNOS in lung. The result showed that DCXC has a potential protective effect on the ALI.

Download Full-text

Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21051795 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1795 ◽

Cited By ~ 1

Author(s):

Rooban B. Nahomi ◽

Mi-Hyun Nam ◽

Johanna Rankenberg ◽

Stefan Rakete ◽

Julie A. Houck ◽

...

Keyword(s):

Knockout Mice ◽

Kynurenic Acid ◽

Ganglion Cells ◽

Ischemia Reperfusion ◽

Fasting Blood Glucose ◽

Kynurenine Pathway ◽

Retinal Ganglion ◽

Diabetic Mice ◽

Wild Type ◽

Ganglion Cell Death

Background: Glaucoma is an optic neuropathy and involves the progressive degeneration of retinal ganglion cells (RGCs), which leads to blindness in patients. We investigated the role of the neuroprotective kynurenic acid (KYNA) in RGC death against retinal ischemia/reperfusion (I/R) injury. Methods: We injected KYNA intravenously or intravitreally to mice. We generated a knockout mouse strain of kynurenine 3-monooxygenase (KMO), an enzyme in the kynurenine pathway that produces neurotoxic 3-hydroxykynurenine. To test the effect of mild hyperglycemia on RGC protection, we used streptozotocin (STZ) induced diabetic mice. Retinal I/R injury was induced by increasing intraocular pressure for 60 min followed by reperfusion and RGC numbers were counted in the retinal flat mounts. Results: Intravenous or intravitreal administration of KYNA protected RGCs against I/R injury. The I/R injury caused a greater loss of RGCs in wild type than in KMO knockout mice. KMO knockout mice had mildly higher levels of fasting blood glucose than wild type mice. Diabetic mice showed significantly lower loss of RGCs when compared with non-diabetic mice subjected to I/R injury. Conclusion: Together, our study suggests that the absence of KMO protects RGCs against I/R injury, through mechanisms that likely involve higher levels of KYNA and glucose.

Download Full-text

Peroxiredoxin-6 protects against mitochondrial dysfunction and liver injury during ischemia-reperfusion in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90583.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. G266-G274 ◽

Cited By ~ 94

Author(s):

Thorsten Eismann ◽

Nadine Huber ◽

Thomas Shin ◽

Satoshi Kuboki ◽

Elizabeth Galloway ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Knockout Mice ◽

Ischemia Reperfusion ◽

Protective Mechanism ◽

Wild Type ◽

Hepatocellular Injury ◽

Hepatic Ischemia ◽

Altered Expression ◽

Peroxiredoxin 6

Hepatic ischemia-reperfusion (I/R) injury is an important complication of liver surgery and transplantation. Mitochondrial function is central to this injury. To examine alterations in mitochondrial function during I/R, we assessed the mitochondrial proteome in C57Bl/6 mice. Proteomic analysis of liver mitochondria revealed 234 proteins with significantly altered expression after I/R. From these, 13 proteins with the greatest expression differences were identified. One of these proteins, peroxiredoxin-6 (Prdx6), has never before been described in mitochondria. In hepatocytes from sham-operated mice, Prdx6 expression was found exclusively in the cytoplasm. After ischemia or I/R, Prdx6 expression disappeared from the cytoplasm and appeared in the mitochondria, suggesting mitochondrial trafficking. To explore the functional role of Prdx6 in hepatic I/R injury, wild-type and Prdx6-knockout mice were subjected to I/R injury. Prdx6-knockout mice had significantly more hepatocellular injury compared with wild-type mice. Interestingly, the increased injury in Prdx6-knockout mice occurred despite reduced inflammation and was associated with increased mitochondrial generation of H2O2 and dysfunction. The mitochondrial dysfunction appeared to be related to complex I of the electron transport chain. These data suggest that hepatocyte Prdx6 traffics to the mitochondria during I/R to limit mitochondrial dysfunction as a protective mechanism against hepatocellular injury.

Download Full-text

Orientin Attenuates Cerebral Ischemia/Reperfusion Injury in Rat Model through the AQP-4 and TLR4/NF-κB/TNF-α Signaling Pathway

Journal of Stroke and Cerebrovascular Diseases ◽

10.1016/j.jstrokecerebrovasdis.2017.05.002 ◽

2017 ◽

Vol 26 (10) ◽

pp. 2199-2214 ◽

Cited By ~ 19

Author(s):

Xiaoru Wang ◽

Fang An ◽

Shulin Wang ◽

Zexin An ◽

Shuhua Wang

Keyword(s):

Cerebral Ischemia ◽

Reperfusion Injury ◽

Signaling Pathway ◽

Rat Model ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Cerebral Ischemia Reperfusion ◽

Tnf Α ◽

Cerebral Ischemia Reperfusion Injury

Download Full-text

Villin and actin in the mouse kidney brush-border membrane bind to and are degraded by meprins, an interaction that contributes to injury in ischemia-reperfusion

AJP Renal Physiology ◽

10.1152/ajprenal.00703.2010 ◽

2011 ◽

Vol 301 (4) ◽

pp. F871-F882 ◽

Cited By ~ 21

Author(s):

Elimelda Moige Ongeri ◽

Odinaka Anyanwu ◽

W. Brian Reeves ◽

Judith S. Bond

Keyword(s):

Brush Border ◽

Knockout Mice ◽

Brush Border Membrane ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Mouse Kidney ◽

Cytoskeletal Proteins ◽

Kidney Tubules ◽

Wild Type

Meprins, metalloproteinases abundantly expressed in the brush-border membranes (BBMs) of rodent proximal kidney tubules, have been implicated in the pathology of renal injury induced by ischemia-reperfusion (IR). Disruption of the meprin β gene and actinonin, a meprin inhibitor, both decrease kidney injury resulting from IR. To date, the in vivo kidney substrates for meprins are unknown. The studies herein implicate villin and actin as meprin substrates. Villin and actin bind to the cytoplasmic tail of meprin β, and both meprin A and B are capable of degrading villin and actin present in kidney proteins as well as purified recombinant forms of these proteins. The products resulting from degradation of villin and actin were unique to each meprin isoform. The meprin B cleavage site in villin was Glu744-Val745. Recombinant forms of rat meprin B and homomeric mouse meprin A had Km values for villin and actin of ∼1 μM (0.6–1.2 μM). The kcat values varied substantially (0.6–128 s−1), resulting in different efficiencies for cleavage, with meprin B having the highest kcat/ Km values (128 M−1·s−1 × 106). Following IR, meprins and villin redistributed from the BBM to the cytosol. A 37-kDa actin fragment was detected in protein fractions from wild-type, but not in comparable preparations from meprin knockout mice. The levels of the 37-kDa actin fragment were significantly higher in kidneys subjected to IR. The data establish that meprins interact with and cleave villin and actin, and these cytoskeletal proteins are substrates for meprins.

Download Full-text